Ethers, Sulfides, Epoxides

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Ethers, Sulfides, Epoxides
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Variety of ethers, ROR
Aprotic solvent
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Reactions of ethers

• Ethers are inert to (do not react with)
• Common oxidizing reagents (dichromate,
  permanganate)
• Strong bases
• Weak acids. But see below.

HX protonates ROH, set-up leaving group followed
by SN2 (10) or SN1 (20 or 30).
Ethers do react with conc. HBr and HI. Recall how
HX reacted with ROH.
Look at this reaction and attempt to predict the
mechanism
Regard as leaving group. Compare to OH, needs
protonation.
Expectations for mechanism Protonation of oxygen
to establish leaving group For 1o alcohols
attack of halide, SN2 For 2o, 3o formation of
carbocation, SN1
Characterize this reaction Fragmentation Substitu
tion
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Mechanism
This alcohol will now be protonated and reacted
with halide ion to yield RX. Inversion will occur.
Inversion of this R group
This alcohol is protonated, becomes carbocation
and reacts with halide.
Loss of chirality at reacting carbon. Possible
rearrangement.
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Properties of ethers

• Aprotic Solvent, cannot supply the H in
  H-bonding, no ether to ether hydrogen bonding
• Ethers are polar and have boiling points close to
  the alkanes.
• propane (bp -42)
• dimethyl ether (-24)
• ethanol (78)

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Hydrogen Bonding
Requirements of Hydrogen Bonding Need both H
acceptor and donor.
protic
Ethers are not protic, no ether to ether H
bonding However, ethers can function as H
acceptors and can engage in H bonding with protic
compounds. Small ethers have appreciable water
solubility.
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Synthesis of ethers
Williamson ether synthesis RO- RX ? ROR
nucleophile
electrophile

• Characteristics
• RO-, an alkoxide ion, is both a strong
  nucleophile (unless bulky and hindered) and a
  strong base. Both SN2 (desired) and E2
  (undesired side product) can occur.
• Choose nucleophile and electrophile carefully.
  Maximize SN2 and minimize E2 reaction by choosing
  the RX to have least substituted carbon
  undergoing substitution (electrophile). Methyl
  best, then primary, secondary marginal, tertiary
  never (get E2 instead).
• Stereochemistry the reacting carbon in R, the
  electrophile which undergoes substitution,
  experiences inversion. The alkoxide undergoes no
  change of configuration.

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• Analysis (devise reactants and be mindful of
  stereochemistry)
• Use Williamson ether synthesis.
• Which part should be the nucleophile?
• Which is the electrophile, the compound
  undergoing substitution?
• Electrophile should ideally be 1o. Maximizes
  subsitution and minimizes elimination.

Provide a synthesis starting with alcohols.
We can set it up in two different ways
Nucleophile
Electrophile, RX undergoing substitution
Remember the electrophile (RX) will experience
inversion. Must allow for that!
1o
1o
or
Nucleophile
Electrophile, RX undergoing substitution
2o
2o
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Electrophile (RX)
SN2
1o
Note allowance for inversion
Nucleophile
2o
Preferably use tosylate as the leaving group, X.
Thus.
TsCl

retention
SN2
Done!
inversion
K
retention
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Acid catalyzed dehydration of alcohols to yield
ethers.

• Key ideas
• Acid will protonate alcohol, setting up good
  leaving group.
• A second alcohol molecule can act as a
  nucleophile. The nucleophile (ROH) is weak but
  the leaving group (ROH) is good.
• Mechanism is totally as expected
• Protonation of alcohol (setting up good leaving
  group)
• For 2o and 3o ionization to yield a carbocation
  with alkene formation as side product. Attack of
  nucleophile (second alcohol molecule) on
  carbocation.
• For 1o attack of nucleophile (second alcohol
  molecule) on the protonated alcohol.

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Mechanism
For primary alcohols.
For secondary or tertiary alcohols.
SN1 substitution H-O-H leaves, R-O-H attached.
E1 elimination
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Use of Mechanistic Principles to Predict Products
protonate
Have set-up leaving group which would yield
secondary carbocation.
Check for rearrangements. 1,2 shift of H. None
further.
Carbocation reacts with nucleophile, another
alcohol.
deprotonate
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Acid catalyzed addition of alcohol to alkene
Recall addition of water to an alkene
(hydration). Acid catalyzed, yielded Markovnikov
orientation. Using an alcohol instead of water
is really the same thing!!
Characteristics Markovnikov Alcohol should be
primary to avoid carbocations being formed from
the alcohol.
Expect mechanism to be protonation of alkene to
yield more stable carbocation followed by
reaction with the weakly nucleophilic alcohol.
Not presented.
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Important Synthetic Technique protecting groups.
Using Silyl ethers to Protect Alcohols
Protecting groups are used to temporarily
deactivate a functional group while reactions are
done on another part of the molecule. The group
is then restored.
Example ROH can react with either acid or base.
We want to temporarily render the OH inert.
Silyl ether. Does not react with non aqueous acid
and bases or moderate aq. acids and bases.
Sequence of Steps
1. Protect
2. Do work
3. Deprotect
THF
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Now a practical example. Want to do this
transformation which uses the very basic
acetylide anion
Replace the H with C2H5
Want to employ this general reaction sequence
which we have used before to make alkynes. We
are removing the H from the terminal alkyne with
NaNH2.
Problem in the generation of the acetylide anion
ROH is stronger acid than terminal alkyne and
reacts preferentially with the NaNH2!
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Solution protect the OH (temporarily convert it
to silyl ether).
Most acidic proton.
Perform desired reaction steps.
Protect, deactivate OH
Remove protection
Alcohol group restored!!
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Revisit Epoxides. Recall 2 Ways to Make Them
Note the preservation of stereochemistry
Epoxide or oxirane
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Use of Epoxide Ring, Opening in Acid
In acid protonate the oxygen, establishing the
very good leaving group. More substituted carbon
(more positive charge although more sterically
hindered) is attacked by a weak nucleophile.
Very similar to opening of cyclic bromonium ion.
Review that subject.
Due to resonance, some positive charge is located
on this carbon.
Inversion occurs at this carbon. Do you see it?
Classify the carbons. S becomes R.
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Epoxide Ring Opening in Base
In base no protonation to produce good leaving
group, no resonance but the ring can open due to
the strain if attacked by good nucleophile. Now
less sterically hindered carbon is attacked.
A wide variety of synthetic uses can be made of
this reaction
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Variety of Products can be obtained by varying
the nucleophile
Attack here
H2O/ NaOH
Do not memorize this chart. But be sure you can
figure it out from the general reaction attack
of nucleophile in base on less hindered carbon

• LiAlH4
• H2O

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An Example of Synthetic Planning
Reactions of a nucleophile (basic) with an
epoxide/oxirane ring reliably follow a useful
pattern.
The epoxide ring has to have been located here
This bond was created by the nucleophile
The pattern to be recognized in the product is
C(-OH) C-Nu
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Synthetic Applications
nucleophile
Realize that the H2NCH2- was derived from
nucleophile CN
N used as nucleophile twice.
Formation of ether from alcohols.
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Epichlorohyrin and Synthetic Planning, same as
before but now use two nucleophiles
Observe the pattern in the product Nu - C C(OH)
C - Nu. When you observe this pattern it
suggests the use of epichlorohydrin.
Both of these bonds will be formed by the
incoming nucleophiles.
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Preparation of Epichlorohydrin
Try to anticipate the products
Recall regioselectivity for opening the cyclic
chloronium ion.
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Example Retrosynthesis Analysis
A b blocker
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Sulfides
Preparation
Symmetric R-S-R Na2S 2 RX ? R-S-R
Unsymmetric R-S-R NaSH RX ? RSH
RSH base ? RS RS- RX ?
R-S-R
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Oxidation of Sulfides